Determination of smoothness of canisters containing inhalable medicaments

ABSTRACT

Disclosed are methods for determining the smoothness index of the interior of a metered dose container.

CROSS REFERENCE TO RELATED APPLICATION

This application claims benefit of priority to U.S. Provisional PatentApplication 60/403,941, filed Aug. 16, 2002.

BACKGROUND OF THE INVENTION

The present invention pertains to aerosol formulations of drugs, such asthose formulations suitable for use in pressurized aerosol metered doseinhalers.

Aerosolized drugs have been used for many years to treat disorders ofthe respiratory system, and as a convenient means for the systemicintroduction of various pharmaceutical agents into the body. The typicalaerosol formulation in a metered dose inhaler for treating disorderssuch as asthma or rhinitis is a suspension of one or more drugsubstances in a fully halogenated (with chlorine and/or fluorine) loweralkyl compound propellant, further containing small amounts ofsurfactants and/or excipients which are usually soluble in thepropellant. Pharmaceutical agents administered by means of metered doseinhalers are usually bronchodilators or corticosteroids.

Typical formulations contain chlorofluorocarbon propellants, the drugsubstance and ethanol, which is miscible with the propellant, andsometimes also contain a surfactant such as oleic acid for maintaining astable suspension, lubrication of the metering valve and otherfunctions.

In general, drug particle sizes from about 1 to about 5 μm are preferredfor administration to the lower airway, with particles smaller thanabout 0.5 μm frequently being exhaled without complete deposition ontissues, while particles larger than about 10 μm can exhibitconsiderable deposition in the mouth and/or pharynx and therefore notreach the lower airway. Very large particles cannot pass through ametering valve and will not be reliably dispensed.

With the implication of fully halogenated chlorofluorocarbon propellantsin the environmentally harmful destruction of ozone in the upperatmosphere, the availability of these propellants has become quiterestricted. This has encouraged development work toward formulationscontaining propellants having reduced upper atmospheric reactivity, suchwork particularly centering about the propellants HFC 134a and HFC 227,these compounds having approximately the same physical properties asthose of the older chlorofluorocarbons used for medicinal aerosols.

Metered dose inhalers typically employ metallic canisters to store themedicament, propellant and excipients. The inner wall of the canistercan, for example, be embedded with various plastic coatings, e.g.Teflon. This aids in preventing deposition of the medicament on to thewall.

It is preferable that the inside of the container or can that is incontact with the medicament be as smooth possible. This is so becauseirregularities in the surface of the container can provide a seed areafor the medicament to first lodge or deposit and eventually grow. Theprocess of mass transfer and consequent deposition of the medicamentcrystals is usually dependent on the crystal size of the medicament, thepresence of impurities, and the temperature of the ambient and surfaceirregularities.

These surface irregularities may provide a locus for the deposition oflarger crystals which have higher settling velocities. These wouldcreate a “mass transfer” boundary layer where mass transfer proceeds bymolecular diffusion. Fluctuations in the ambient temperature, asencountered during shipping and handling, can lead to crystal growth,the activation energy for which is temperature dependent and follows theArrhenius equation. These “growing” crystals would also remainlodged/deposited on the surface imperfection and thus become unavailablefor delivery. Therefore overtime, this phenomenon of can wall depositioncan lead to a decrease in the amount of medicament that is dispensed tothe patient.

There thus exists a need for dosing systems having canisters with smoothinteriors that minimize the possibility of can wall deposition by notproviding the locii for crystal deposition such that it is ensured thatthe patient receives the requisite amount of medication.

SUMMARY OF THE INVENTION

Accordingly, there is disclosed a method for determining a smoothnessindex of a metered dose container having an inner core comprising thesteps of subjecting said inner core of said metered dose container toreflected light photomicrography to obtain a digital image containing aplurality of pixels of said inner core, determining from said digitalimage the brightness of each of said pixels and quantifying saidbrightness by assigning an integer value thereto, wherein said valuecorresponds to an amount of brightness and comparing said brightness ofsaid pixel to a reference standard to determine the smoothness index ofsaid inner core of said metered dose container.

There is also disclosed a method for determining a smoothness index of ametered dose container having an inner core comprising the steps ofsubjecting said inner core of said metered dose container containing atleast one pharmacologically active agent to reflected lightphotomicrography to obtain a digital image containing a plurality ofpixels of said inner core, determining from said digital image thebrightness of each of said pixels and quantifying said brightness byassigning an integer value thereto, wherein said value corresponds to anamount of brightness and comparing said brightness of said pixel to areference standard to determine the smoothness index of said inner coreof said metered dose container.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the manner in which a digital micrograph (i.e., adigital image containing a plurality of pixel of the inner core) isobtained from a sample of an inner core (from a metered dose container)based on reflected light photomicrography wherein a smoothness index iscalculated.

BRIEF DESCRIPTION OF THE DIGITAL MICROGRAPHS

FIG. 2 is of an epoxy coated can with imperfections.

FIG. 3 is of an FEP coated can.

FIG. 4 is of a PFA coated can with non-optimized coating.

FIG. 5 is of a PFA coated can with optimized coating.

FIG. 6 is of an Epoxy coated can with drug.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, there is disclosed the use of reflected lightphotomicrography and digital image analysis as a quantitative andqualitative measure of the surface smoothness of coated and uncoatedcans used for the packaging of pressurized aerosols.

A qualitative and quantitative physical description of surface'ssmoothness is defined in this invention as a Smoothness Index. Thepresent invention is based upon the use of reflected light in amicroscope to obtain a digital image and process this image utilizingimage processing. Image processing manipulates information within animage to make it more useful; digital image processing is a specifictype of image processing performed with a computer.

The image is thereafter digitized whereby the image is divided into ahorizontal grid, or array, of very small regions called pixels (pictureelements). In the computer the image is represented by this digitalgrid, or bitmap. Each pixel in the bitmap is identified by its positionin the grid, as referenced by its row (x) number and column (y) number.When a source image, such as a photograph, is digitized, it is examinedin grid fashion. That is, each pixel in the image is individuallysampled, and it brightness is measured and quantified.

This measurement results in a value for the pixel, usually an integer,which represents the brightness or darkness of the image at that point.This value is stored in the corresponding pixel of the computer's imagebit map. It is these areas of brightness and darkness that were used forthe qualitative and quantitative evaluation of the amount of lightreflected off the studied surfaces, and hence their smoothness. Thebrighter the area in the image, the more light is reflected, andtherefore, the smoother it is; the darker the area in the image is, theless light is reflected, and therefore, the less smooth it is. Theintegers, obtained for the studied surfaces, representing the amount ofreflected light are compared to the integer obtained from aluminum foil,used as a standard reference material for reflection of light.

The ratio of the integer for the studied surface to the integer obtainedfor the aluminum foil was called the “Smoothness Index,” the closer theratio to one the brighter, and hence, the smoother the surface is. Thesmoothness index is defined as follows:Smoothness Index=Amount of Reflected Light from the StudiedSurface÷Amount of Light Reflected from Aluminum Foil Standard

Advantages of the present invention included the ability to distinguishbetween cans used for MDI products, with various surface smoothness,i.e., possible imperfection in the surface of cans coated with the samematerial, e.g., epoxy coated cans. See FIG. 2. Another feature of theinvention is to distinguish between cans coated with various materials,e.g., epoxy coated versus teflon coated. See FIGS. 2 and 3. Anotheradvantage of the invention is to distinguish between cans coated withthe same material such as teflon, but cured at different conditions. SeeFIGS. 4 and 5. Another advantage of the invention is to detect drugdeposition on the surface of these cans. See FIG. 6.

The canisters of the present invention can have an inner core that ispreferably embedded with various forms of Teflon. As used herein, TeflonPTFE is defined as polytetrafluoroethylene; Teflon FEP is defined asfluorinated ethylene copolymer; Teflon PFA is defined as perfluoroalkoxyethylene propylene copolymer; and Teflon ETFE is defined as a copolymerof ethylene and tetrafluoroethylene. The inner core may also be embeddedor treated with other coatings and/or materials such as lacquer, epoxyresin and other materials as known to one of the art.

Preferably, the method in accordance with the present invention analyzesdosing systems that employ a canister containing at least onepharmacologically active agent or drug that is a material capable ofbeing administered to the respiratory system, including the lungs. Forexample, a drug in accordance with the present invention could beadministered so that it is absorbed into the blood stream through thelungs. Particularly preferred pharmacologically active agents inaccordance with the present invention include, without limitation,corticosteroids such as: mometasone furoate anhydrous; beclomethasonedipropionate; budesonide; fluticasone; dexamethasone; flunisolide;triamcinolone;(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione;tipredane and the like. Mometasone furoate anhydrous is the mostpreferred and is available from Schering-Plough Corporation.

β-agonists (including β₁ and β₂-agonists) including, without limitation,albuterol, terbutaline, salmeterol, and bitolterol may also beadministered with the present invention. Formoterol (also known aseFormoterol) e.g., as the fumarate or tartrate, a highly selectivelong-lasting β₂-adrenergic agonist having bronchospasmolytic effect, iseffective in the treatment of reversible obstructive lung ailments ofvarious genesis, particularly asthmatic conditions and may also beadministered with the present invention. Another long-acting β-agonistwhich can be administered in accordance with the present invention isknown as TA-2005, chemically identified as 2(1H)-Quinolinone,8-hydroxy-5-[1-hydroxy-2-[[2-(4-(methoxyphenyl)-1-methylethyl]amino]ethyl]-monohydrochloride,[R—(R*,R*)]-.

Anticholinergics such as ipratropium bromide and oxitropium bromide maybe used in the present invention. So, too can sodium cromoglycate,nedocromil sodium and leukotriene antagonists such as montelukast,zafirlukast and pranlukast. Bambuterol (e.g. as hydrochloride),fenoterol (e.g. hydrobromide), clenbuterol (e.g. as hydrochloride),procaterol (e.g. as hydrochloride), and broxaterol are highly selectiveβ₂-adrenergic agonists can be administered.

Several of these compounds could be administered in the form ofpharmacologically acceptable esters, salts, solvates, such as hydrates,or solvates of such esters or salts, if any. The term is also meant tocover both racemic mixtures as well as one or more optical isomers.

The canister containing a drug in accordance with the present inventioncan also be an inhalable protein or a peptide such as insulin,interferons, calcitonins, parathyroid hormones, granulocytecolony-stimulating factor and the like. “At least one pharmacologicallyactive agent” as used herein may refer to a single pharmacologicallyactive entity, or to combinations of any two or more, an example of auseful combination being a dosage form including both a corticosteroidand a β-agonist.

Also within the scope of the present invention are the analysis ofcanisters containing combinations of any of the above pharmaceuticalproducts, e.g. a corticosteroid may be combined with a β-agonist in asingle formulation. One such preferred combination is that of mometasonefuroate anhydrous with formoterol fumarate.

The amount of drug administered will vary with a number of factorsincluding, without limitation, the age, sex, weight, condition of thepatient, the drug, the course of treatment, the number of doses per dayand the like. For example, for mometasone furoate anhydrous, the amountof drug delivered per dose, i.e. per inhalation, will generally rangefrom about 10 μg to about 10,000 μg. Doses of 25 μg, 50 μg, 75 μg, 100μg, 125 μg, 150 μg, 175 μg, 200 μg, 250 μg, 300 μg, 400 μg and/or 500 μgare preferred.

To be topically effective in the lungs or the upper and/or lower airwaypassages, it is important that the pharmacologically active agent bedelivered as particles of about 10 μm or less. The ability of a dosageform to actually administer free particles of these therapeuticallyeffectively sized particles is the fine particle fraction. Fine particlefraction is, therefore, a measure of the percentage of bound drugparticles released as free particles of drug having a particle sizebelow some threshold during administration. Fine particle fraction canbe measured using a multi-stage liquid impinger manufactured by CopleyInstruments (Nottingham) LTD using the manufacturer's protocols. Inaccordance with the present invention, an acceptable fine particlefraction is at least 10% by weight of the drug being made available asfree particles having an aerodynamic particle size of 6.8 μm, or less,measured at a flow rate of 60 liters per minute.

Propellant-based pharmaceutical aerosol formulations in the art use amixture of liquid chlorofluorocarbons as the propellant.Fluorotrichloromethane, dichlorodifluoromethane anddichlorotetrafluoroethane are the most commonly used propellants inaerosol formulations for administration by inhalation. Suchchlorofluorocarbons (CFCs), however, have been implicated in thedestruction of the ozone layer and their production is being phased out.Hydrofluorocarbon 134a, also known as 1,1,1,2-tetrafluoroethane or HFC134a, and hydrofluorocarbon 227a, also known as1,1,1,2,3,3,3-heptafluoropropane or HFC 227, are said to be less harmfulto the ozone than many chlorofluorocarbon propellants, and both ormixtures thereof are considered to be used within the scope of thepresent invention.

The formulations of the present invention may be filled into the aerosolcontainers using conventional filling equipment. Since propellants 227and 134 may not be compatible with all elastomeric compounds currentlyutilized in present aerosol valve assemblies, it may be necessary tosubstitute other materials, such as white buna rubber, or to utilizeexcipients and optionally surfactants which mitigate the adverse effectsof propellant 227 or 134 on the valve components.

The excipient facilitates the compatibility of the medicament with thepropellant and also lowers the discharge pressure to an acceptablerange, i.e., about 2.76−5.52×10⁵ newton/meter² absolute (40 to 80 psi),preferably 3.45–4.83×10⁵ newton/meter² absolute (50 to 70 psi). Theexcipient chosen must be non-reactive with the medicaments, relativelynon-toxic, and should have a vapor pressure below about 3.45×10⁵newton/meter² absolute (50 psi).

As used hereinafter the term “medium chain fatty acids” refers to chainsof alkyl groups terminating in a —COOH group and having 6–12 carbonatoms, preferably 8–10 carbon atoms. The term “short chain fatty acids”refers to chains of alkyl groups terminating in a —COOH group and having4–8 carbon atoms. The term “alcohol” includes C₁–C₃ alcohols, such asmethanol, ethanol and isopropanol.

Among the preferred excipients are: propylene glycol diesters of mediumchain fatty acids available under the tradename Miglyol 840 (from HulsAmerica, Inc. Piscataway, N.J.); triglyceride esters of medium chainfatty adds available under the tradename Miglyol 812 (from Huls);perfluorodimethylcyclobutane available under the tradename Vertrel 245(from E.I. DuPont de Nemours and Co. Inc. Wilmington, Del.);perfluorocyclobutane available under the tradename octafluorocyclobutane(from PCR Gainsville, Fla.); polyethylene glycol available under thetradename EG 400 (from BASF Parsippany, N.J.); menthol (fromPluess-Stauffer International Stanford, Conn.); propylene glycolmonolaurate available under the tradename lauroglycol (from GattefosseElmsford, N.Y.); diethylene glycol monoethylether available under thetradename Transcutol (from Gattefosse); polyglycolized glyceride ofmedium chain fatty adds available under the tradename Labrafac Hydro WL1219 (from Gattefosse); alcohols, such as ethanol, methanol andisopropanol; eucalyptus oil available (from Pluses-StaufferInternational); and mixtures thereof.

A surfactant is frequently included in aerosol formulations, forpurposes such as assisting with maintaining a stable suspension of thedrug and lubricating the metering valve. The formulation of the presentinvention does not require a surfactant for maintenance of readydispersability (such as by moderate agitation immediately prior to use),as the drug forms loose flocculates in the propellant and does notexhibit a tendency to settle or compact. Upon undisturbed storage, thedrug particles remain suspended in their flocculated state. Among thepreferred surfactants are: oleic acid available under the tradenameoleic acid NF6321 (from Henkel Corp. Emery Group, Cincinnati, Ohio);cetylpyridinium chloride (from Arrow Chemical, Inc. Westwood, N.J.);soya lecithin available under the tradename Epikuron 200 (from LucasMeyer Decatur, Ill.); polyoxyethylene (20) sorbitan monolaurateavailable under the tradename Tween 20 (from ICI Specialty Chemicals,Wilmington, Del.); polyoxyethylene (20) sorbitan monostearate availableunder the tradename Tween 60 (from ICI); polyoxyethylene (20) sorbitanmonooleate available under the tradename Tween 80 (from ICI);polyoxyethylene (10) stearyl ether available under the tradename Brij 76(from ICI); polyoxyethylene (2) oleyl ether available under thetradename Brij 92 (frown ICI);Polyoxyethylene-polyoxypropylene-ethylenediamine block copolymeravailable under the tradename Tetronic 150 R1 (from BASF);polyoxypropylene-polyoxyethylene block copolymers available under thetradenames Pluronic L-92, Pluronic L-121 end Pluronic F 68 (from BASF);castor oil ethoxylate available under the tradename Alkasurf CO-40 (fromRhone-Poulenc Mississauga Ontario, Canada); and mixtures thereof.

When mometasone is used, it is known that it has some solubility inethanol. As with other drugs which have solubility in ethanol, there isa tendency for mometasone furoate to exhibit crystal growth inethanol-containing formulations. Formulation parameters which do notpromote drug particle size growth are known. These parameters providethe advantage of minimizing the required ethanol concentrations, toreduce the potential for unpleasant taste sensations and render thecompositions more suitable for use by children and others with lowalcohol tolerance.

A certain minimum level of ethanol is preferred to provide consistentand predictable delivery of the drug from a metered dose dispenser. Thisminimum level is about 1 weight percent of the total formulation, whichresults in a marginally acceptable drug delivery. Increased amounts ofethanol generally improve drug delivery characteristics. However, and toprevent drug crystal growth in the formulation, it is preferred to limitthe concentration of ethanol. Experimental data indicate that the ratioof the weight of mometasone furoate to the weight of ethanol isimportant in preventing particle size increases.

Formulations of the invention are made according to procedures customaryin the art for other aerosol compositions. Typically, all componentsexcept the propellant are mixed and introduced into aerosol containers.The containers can then be chilled to temperatures below the boilingpoint of the propellant, and the required amount of the chilledpropellant added before the metering valve is crimped on to thecontainer. Alternatively, the containers can be fitted with a meteringvalve before being filled with propellant, and the required quantity ofpropellant will be introduced through the valve. The available meteringvalve delivery volumes range from about 25 to about 100 microliters peractuation, while the amounts of drug substance required in a dose fortreating a particular condition is generally about 10 to about 500micrograms per valve actuation. These two factors combined poselimitations that dictate the points within the foregoing ethanolparameters for a given formulation. The determination of such amounts iswithin the skill of workers in this art.

Depending on the particular application, the container may be chargedwith a predetermined quantity of formulation for single or multipledosing. Typically, the container is sized for multiple-dosing, and,therefore it is very important that the formulation delivered issubstantially uniform for each dosing. For example, where theformulation is for bronchodilation, the container typically is chargedwith a sufficient quantity of the formulation for 200 charges.

Suitable suspensions may be screened in part by observing severalphysical properties of the formulation, i.e. the rate of particleagglomeration, the size of the agglomerates and the rate of particulatecreaming/settling and comparing these to an acceptable standard. Such,suitable solutions may be screened/evaluated by measuring the solubilityof the medicament over the entire recommended storage temperature range.

Suspensions of the present invention preferably may be prepared byeither the pressure filling or cold filling procedures known in the art.

For metered dose inhalers, suspensions may be particularly preferred forefficacy and stability considerations.

Those skilled in the art may choose to add one or more preservative,buffer, antioxidant, sweetener and/or flavors or other taste maskingagents depending upon the characteristics of the formulation.

The invention will be further described by means of the followingexamples, which are not intended to limit the invention, as defined bythe appended claims, in any manner.

EXAMPLE 1

Optical microscopy was performed using an Olympus BX60 model polarizedlight microscope; photomicrography was performed using a digital camera(DP 10-32); Image analysis of the generated image was performed usingImagePro Plus software on a Dell OptiPlex GX1 computer with a PentiumIII microprocessor; Two stage filling was performed by filling withPamasol.

The following ingredients and packages were utilized:

a) Teflon coated 14 mL cans from CCL (PFA);

b) Teflon coated 14 mL cans from Presspart (PFA optimized curingprocess);

c) Teflon coated 14 mL cans from CCL (FEP same as PFA without themelanine;

d) Epoxy coated 10 mL cans from Safet;

e) 25 μL valves from Valois;

f) 63 μL valves from Valois;

g) Mometasone furoate micronized drug substance;

h) Alcohol USP 200 proof;

i) Oleic acid NF (Emersol 6321);

j) HFC-227 propellant;

k) Pamasol Macromat Line 4400 from D.H. Industries Limited; and

l) Aluminum foil sheets.

The following filling procedure was applied: Drug concentrate(Mometasone furoate micronized in alcohol USP 200 proof with oleic acidNF (Emersol 6321)) was prepared in three concentrations 1.81 mg/g, 0.96mg/g and 0.28 mg/g, and then metered into cans. The first twoconcentrations were metered into epoxy coated 10 mL cans while the thirdconcentrate was metered into 14 mL teflon FEP cans and 14 mL teflon PEFcans. The cans were crimped with the 25 μL valves (the first twoconcentrations) and the 63 μL (the third concentration). The HFC-227propellant was filled in to these cans up to 8 g total fill (the firsttwo concentrations) and up to a 15 g fill (the third concentration).

The cans were then cut open to analyze the effect of the drug on thereflection from the can surfaces. The internal surface studied was thebottom flat part of the can. This approach was pursued to avoidspherical aberration interference. Spherical aberration is the mostserious imperfection that occurs during reflection off a surface wherebylight rays from a single point in the object are reflected from theouter zone of a spherical surface and are not focused at the same pointas the central rays.

The following procedure was used to obtain the digital micrographs:

Turn on the microscope. Insert the card into the camera and close thecard cover. The main switch on the camera must be in the off position.Turn on the camera. Press the light intensity “Preset” button whilemaking sure that the Transmitted/Reflected light selector switch is inthe Reflected light position. Push the Aperture Iris (AS) and the FieldIris (FS) Diaphragm knobs as well as the (SHUTTER) knob leaving thediaphragms open. Adjust the Light Path Selector knob to the middleposition. Disengage the Analyzer and the Polarizer sliders from thelight path by sliding the filters out.

Next, remove the Differential Interference Contrast Prism from the lightpath by sliding the prism out until there is a click and the engravingcan be seen. Tighten the clamping screw to secure the prism. Engage theLBD (color balance and filter) built-in filter by turning its lever sothat the reference mark on the lever is aligned with the reference markon the base.

Then, disengage the ND25 (natural density filter number 25) and ND6(natural density filter number 6) by turning their levers so that thereference marks are aligned with the reference marks on the base. Placethe dummy plate on the stage and secure it with the specimen holders.Place the N 9.50 Munsell color standard (white surface up) on the stage.Turn the nosepiece to engage the 5× objective.

Select picture quality by switching the manual switch box to Super HighQuality (SHQ) in the menu screen. Record mode should be activated. Movethe N 9.50 Munsell color standard with the white surface up to thecenter and directly under the light and press the Auto Exposure Lock (AELOCK) button to lock the exposure time and brightness of the imagecenter.

Place the standard sample on the stage and focus the image with thecoarse adjustment knob and then with the fine adjustment knob. Press theExposure (EXPOSE) button to take a single picture. To preview thepicture, press the REC/PLAY button. Press REC/PLAY button to switch backto record mode. Repeat the steps in this paragraph for the rest of thesamples.

Thereafter, retrieve the picture from the database. Then, analyze theimage's brightness using the ImagePro Plus software.

The smoothness index is defined as follows:Smoothness Index=Amount of Reflected Light from the StudiedSurface÷Amount of Light Reflected from Aluminum Foil Standard

The following samples were analyzed:

Each sample was photographed, the image was digitized and the digitalimage was then analyzed using the ImagePro Plus software for the areasof brightness and darkness. The average measurement of the area ofbrightness is presented in pixels, i.e., for each sample the number of“bright” pixels were added. These were then divided by the number ofmeasurements and an average was obtained. The samples that showed thehigher numbers were brighter than the ones with lower numbers. Forinstance Teflon—Standard—FEP exhibited the highest average number of“bright area” pixels (181.9 pixels) and therefore had the smoothestsurface. The Teflon-PFA non-optimized was found to be least bright andhad the lowest average number of “bright area” pixels (111.7 pixels).The significance of this finding is that the technique is capable ofcharacterizing the quality of the studied can wall surface. In additionthe “Smoothness Index” is capable of quantifying the difference in thequality of the can wall surfaces. These data are shown in Table 1.

TABLE 1 Can Type Average Reflection (Pixels) Epoxy Can 132.8 Teflon PFACan 111.7 non-optimized Teflon PFA Can 171.5 optimized Teflon FEP Can181.9 Aluminum Foil 249.6

Each can type, Epoxy coated, Teflon-PFA and Teflon-FEP werephotographed, the image was digitized, and the digital images wereanalyzed for their bright area pixels as described in the previousparagraph (Table 2). The same types of cans were then analyzed in thepresence of known concentrations of drug. The pressurized cans werechilled, then cut open and the propellant was left to evaporate. Thenthe same section of the can (base) was analyzed for the average area ofbrightness. These areas in the presence of drug were invariably lessbright when compared to the same areas in the absence of drug.

The least bright were the Teflon-PFA coated cans in the presence of drugwhich showed a 35% reduction in reflection when compared to the samecans in the absence of drug. The Teflon-FEP coated cans in the presenceof drug showed an intermediate brightness and a 33% reduction inbrightness when compared to the same cans in the absence of drug.Surprisingly the brightest were the Epoxy cans in the presence of drugand showed the least reduction in brightness (3%). These data arepresented in Table 2.

TABLE 2 % Reduction Average Smooth- in Reflection Reflection Standardness Due to Drug Can Type (Pixels) (Pixels) Index Adhesion Epoxy Can132.8 249.6 0.53 N/A (76588-054) Epoxy Can 128.7 249.6 0.52  3% (withDrug 1.813 mg/g) Teflon PFA Can 171.5 249.6 0.69 N/A optimized TeflonPFA Can 111.7 249.6 0.43 35% optimized (with Drug 1.813 mg/g) Teflon FEPCan 181.9 249.6 0.73 N/A Teflon FEP Can 121.4 249.6 0.54 33% (with Drug1.813 mg/g) Aluminum Foil 249.6 249.6 1 N/A

Aluminum foil was used as a reference standard for a surface that wouldreflect most. And indeed its reflection (249.6 pixels) was very close tothe digital camera's resolution limit of 250 pixels. All consequentmeasurements were compared to this standard using the “Smoothness Index”equation. Therefore, the closer the ratio to unity the brighter was thestudied sample/surface.

The foregoing descriptions of various embodiments of the invention arerepresentative of various aspects of the invention, and are not intendedto be exhaustive or limiting to the precise forms disclosed. Manymodifications and variations undoubtedly will occur to those havingskill in the art. It is intended that the scope of the invention shallbe fully defined solely by the appended claims.

1. A method for determining a smoothness index of a metered dosecontainer having an inner core, comprising the steps of: a) subjectingsaid inner core of said metered dose container containing at least onepharmacologically active agent, wherein the at least onepharmacologically active agent is a corticosteroid selected from thegroup consisting of mometasone furoate anhydrous; beclomethasonedipropionate; budesonide; fluticasone; dexamethasone; flunisolide;triamcinolone;(22R)-6α,9α-ditluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione;and tipredane, to reflected light photomicrography to obtain a digitalimage containing a plurality of pixels of said inner core; b)determining from said digital image the brightness of each of saidpixels and quantifying said brightness by assigning an integer valuethereto, wherein said value corresponds to an amount of brightness: andc) comparing said brightness of said pixel to a reference standard todetermine the smoothness index of said inner core of said metered dosecontainer.
 2. The method for determining a smoothness index of a metereddose container having an inner core according to claim 1, whereincorticosteroid is mometasone furoate anhydrous.
 3. The method fordetermining a smoothness index of a metered dose container having aninner core according to claim 1, wherein the corticosteroid isbeclomethasone diproprionate.
 4. The method for determining a smoothnessindex of a metered dose container having an inner core according toclaim 1, wherein the corticosteroid is budesonide.
 5. The method fordetermining a smoothness index of a metered dose container having aninner core according to claim 1, wherein the corticosteroid isfluticasone.
 6. A method for determining a smoothness index of a metereddose container having an inner core, comprising the steps of: a)subjecting said inner core of said metered dose container containing atleast one pharmacologically active agent, wherein the at least onepharmacologically active agent is a β-agonist selected from the groupconsisting of albuterol, terbutaline, salmeterol, bitolterol,formoterol, eFormoterol, 2(1H)-Quinolinone,8-hydroxy-5-[1-hydroxy-2-[[2-(4-(methoxmhenyl)-1-methylethyl]amino]ethyl]monohydrochloride,[R—(R*,R*)]-, to reflected light photomicrography to obtain a digitalimage containing a plurality of pixels of said inner core; b)determining from said digital image the brightness of each of saidpixels and quantifying said brightness by assigning an integer valuethereto, wherein said value corresponds to an amount of brightness: andc) comparing said brightness of said pixel to a reference standard todetermine the smoothness index of said inner core of said metered dosecontainer.
 7. The method for determining a smoothness index of a metereddose container having an inner core according to claim 6, whereinβ-agonist is albuterol.
 8. The method for determining a smoothness indexof a metered dose container having an inner core according to claim 6,wherein the β-agonist is terbutaline.
 9. The method for determining asmoothness index of a metered dose container having an inner coreaccording to claim 6, wherein β-agonist is formoterol.
 10. The methodfor determining a smoothness index of a metered dose container having aninner core according to claim 6, wherein the β-agonist is salmeterol.11. A method for determining a smoothness index of a metered dosecontainer having an inner core comprising the steps of: a) subjectingsaid inner core of said metered dose container containing at least onepharmacologically active agent, wherein the at least onepharmacologically active agent is selected from the group consisting ofipratropium bromide, oxitropium bromide, sodium cromoglycate, nedocromilsodium, montelukast, zafirlukast, pranlukast, bambuterol, fenoterol,clenbuterol, procaterol and broxyterol, to reflected lightphotomicrography to obtain a digital image containing a plurality ofpixels of said inner core; b) determining from said digital image thebrightness of each of said pixels and quantifying said brightness byassigning an integer value thereto, wherein said value corresponds to anamount of brightness: and c) comparing said brightness of said pixel toa reference standard to determine the smoothness index of said innercore of said metered dose container.
 12. The method for determining asmoothness index of a metered dose container having an inner coreaccording to claim 11, wherein the at least one pharmacologically activeagent is montelukast.
 13. A method for determining a smoothness index ofa metered dose container having an inner core comprising the steps of:a) subjecting said inner core of said metered dose container containingat least one pharmacologically active agent, wherein the at least onepharmacologically active agent is selected from the group combination ofa corticosteroid and a β-agonist, to reflected light photomicrography toobtain a digital image containing a plurality of pixels of said innercore; b) determining from said digital image the brightness of each ofsaid pixels and quantifying said brightness by assigning an integervalue thereto, wherein said value corresponds to an amount ofbrightness: and c) comparing said brightness of said pixel to areference standard to determine the smoothness index of said inner coreof said metered dose container.
 14. The method for determining asmoothness index of a metered dose container having an inner coreaccording to claim 13, wherein the corticosteroid is mometasone furoateanhydrous and the β-agonist is formoterol.
 15. The method fordetermining a smoothness index of a metered dose container according toclaim 13, wherein the corticosteroid is budesonide and the β-agonist isterbutaline.
 16. The method for determining a smoothness index of ametered dose is container having an inner core according to claim 13,wherein the corticosteroid is fluticasone and the β-agonist issalmeterol.